September 8, 2008 — High serum levels of calcium might increase the risk for fatal prostate cancer, a new study suggests. If the finding is confirmed, it might be possible to reduce the risk for fatal prostate cancer by using drugs to lower serum levels of calcium and/or parathyroid hormone (PTH), say the researchers.
"Our study shows that calcium at the high end of normal is associated with a 3-fold increased risk for fatal prostate cancer later in life," says lead researcher Gary G. Schwartz, PhD, associate professor of cancer biology and epidemiology and prevention at Wake Forest University Baptist Medical Center, in Winston-Salem, North Carolina. The finding is reported in the September issue of Cancer Epidemiology, Biomarkers & Prevention.
"This may be a risk factor that — for the first time — we can do something about," Dr. Schwartz commented in an interview. The other risks factors for prostate cancer (i.e., family history, age, and race) cannot be altered, but this one can, he said. If the finding is confirmed in other studies, then in the future drugs could be used to lower these high levels of calcium. Such drugs include calcitriol, paricalcitol, doxercalciferol, and cinacalcet, which are already used in patients with high levels of ... PTH, such as those with chronic kidney disease,” he said.
"The take-home message is that this may offer a simple means to detect men who are at an increased risk of fatal prostate cancer," said coauthor Halcyon Skinner, PhD, from the department of population health sciences at the University of Wisconsin–Madison. He emphasized, however, that there is little correlation between calcium in the blood and calcium in the diet. "So men needn't be concerned about reducing their ordinary intakes of calcium," he said in a statement.
Link With Fatal Cancer, Not Incidence
The team analyzed data on 2814 men who had participated in the National Health and Nutrition Examination Survey (NHANES-1) and found 85 cases of prostate cancer and 25 deaths from prostate cancer. The team also looked at serum calcium levels in blood samples taken an average of 9.9 years before prostate cancer was diagnosed and found that men with higher levels had a significantly higher risk for fatal prostate cancer. These men had calcium levels in the range of 9.9 to 10.5 mg/dL, which the researchers described as the "high end of the normal range."
"Our results are based on a small number of fatal cases (n = 25), and require confirmation by other prospective studies," the researchers emphasize. "One swallow does not make a summer," Dr. Schwartz commented, and he stressed that it is too early to make any clinical changes on the basis of these results.
"I think the findings are original and intriguing," said Tomasz M. Beer, MD, Grover C. Bagby Endowed Chair for Prostate Cancer Research and Associate Professor of Medicine, Oregon Health & Science University, Portland, who was approached for comment. "As the authors indicated, they are based on a relatively small number of prostate cancer cases and deaths. There are also other limitations to the NHANES study. Thus, the results should be viewed as hypothesis-generating and not yet definitive."
"Having said that, the results are very interesting and the hypothesis should be examined in other studies," Dr. Beer commented to Medscape Oncology. "If confirmed, they could both help us better predict risk of the disease and formulate new insights into the biologic basis of prostate cancer."
"This is a fascinating finding," agrees John Barron, MD, Dartmouth Medical School. He says it will be a challenge to integrate this finding with previous research regarding prostate cancer, but it "could provide a new clue to advanced prostate cancer."
Dr. Schwartz and colleagues point out that their finding is consistent with the results of a large population-based study of serum calcium and survival from Sweden (J Clin Endocrinol Metab. 1996;81:2149-2153). That study found a link between increased cancer mortality in men with serum calcium in the upper reference range (10 mg/dL). In both studies, the link was with fatal cancer, not the incidence of cancer.
High calcium levels and high levels of PTH might stimulate the growth of prostate cancer cells, Dr. Schwartz explained. This has been shown in the laboratory.
However, there is much more to the calcium/PTH and prostate cancer story, and some of the complexities are outlined in an article also published in the September issue of Cancer Epidemiology, Biomarkers & Prevention (2008;17:478-483).
Secondary Parathyroidism and Potential for Intervention
Prostate cancer is unusual in that metastases to the bone are predominantly blastic (bone-forming), Dr. Schwartz explained. This is in contrast with the bone metastases seen with breast, colon, and lung cancers, for example, which produce lytic lesions.
These prostate cancer bony metastases show an increased expression of the PTH receptor, and PTH promotes the growth and invasiveness of prostate cancer cells in bone. Hence, these blastic metastases appear to induce a "vicious cycle," in which PTH resorbs normal bone to support the growth of blastic bone.
The result is that prostate cancer bone metastases raise levels of serum PTH, and patients develop secondary hyperparathyroidism. This observation is well known, but the clinical implications have been "little appreciated," Dr. Schwartz said. "Recognizing this potential role of PTH in the progression of skeletal metastases suggests novel opportunities for prostate cancer secondary prevention. In particular, we propose that suppressing serum PTH in prostate cancer may reduce morbidity by decreasing fractures and pain caused by bone resorption, and may reduce mortality by retarding the progression of metastatic disease."
A clinical trial to test this hypothesis is about to begin, Dr. Schwartz noted. It will involve 30 men with advanced prostate cancer and elevated levels of PTH and will use paricalcitol, which lowers serum levels of PTH.
The researchers have disclosed no relevant financial relationships.
Cancer Epidemiol Biomarkers Prev. 2008;17:2302-2305.
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